1. Field of the Invention
The present invention concerns methods and compositions for treating human immunodeficiency virus (HIV) in infected subjects. Preferably, the methods and compositions utilize complexes made by the dock-and-lock (DNL) technique. In particular embodiments, the DNL complexes comprise antibodies or antibody fragments, which include those against HIV envelope antigens, for example anti-gp120 or anti-gp41 antibodies such as P4/D10, 2G12, 2F5 or 4E10, and other antibodies of interest, such as epratuzumab (anti-CD22) and milatuzumab (anti-CD74). In more particular embodiments, the DNL complex may comprise one or more agents, such as therapeutic agents, diagnostic agents, virostatic agents and/or cytotoxic agents, including but not limited to chemotherapeutic agents such as doxorubicin. Such agents may be incorporated into the DNL complex using the DDD (docking and dimerization domain) and AD (anchoring domain) binding interaction described below, or may be directly conjugated to the DNL complex. More preferably, the DNL complex may comprise one or more agents known to have anti-HIV activity, such as the T20 (enfuvirtide) HIV fusion inhibitor. Most preferably, incorporation of anti-HIV agents into a DNL complex improves the pharmacokinetic properties of the agent, for example by increasing its serum half-life, allowing less frequent dosing and/or improved efficacy. In alternative embodiments, the DNL complex may comprise one or more polyethylene glycol (PEG) moieties to improve pharmacokinetics and reduce immunogenicity. The DNL complexes may be used alone or in combination with one or more known anti-HIV agents.
2. Description of Related Art
Despite encouraging advances in the treatment of human immunodeficiency virus-1 (HIV-1) with anti-retroviral therapy (ART), analyses of peripheral blood and lymph nodes have documented the presence of persistent reservoirs of resting T cells which harbor latent provirus that can activate spontaneously even years after the termination of therapy (Berger et al., Proc Natl Acad Sci USA 1998, 95:11511-11513; Blankson et al., Annu Rev Med 2002, 53:557-593).
Depending on its binding specificity and effector functions, an antibody can be useful for preventing the infection of HIV by blocking the viral entry into target cells, evoking complement-mediated virolysis of free virions (Parren et al., AIDS 1999, 13[Suppl A]:S137-162), and/or inducing Fc receptor-mediated activities (Forthal and Moog, Curr Opin HIV AIDS 2009, 4: 388-393), which include antibody-dependent cellular cytotoxicity (ADCC) to kill infected cells, inhibition and neutralization of HIV on antigen presenting cells, and antibody-dependent cell-mediated virus inhibition (ADCVI)). To date, the use of anti-viral antibodies for immunotherapy of patients infected with HIV has not fulfilled its initial promise (Hinkula et al., J Acquir Immune Defic Syndr 1994, 7:940-951; Trkola et al., Nat Med 2005, 11:615-622).
Attempts have been made to use various viral or cellular components as targets for antibody delivery of therapeutic agents to HIV-infected cells (Davey et al., J Infect Dis 1994, 170:1180-1188; Pincus et al., J Immunol 2003, 170:2236-2241; Ramachandran et al., J Infect Dis 1994, 170:1009-1013; Saavedra-Lozano et al., Proc Natl Acad Sci USA 2004, 101:2494-2499). Similar immunotoxins have proved promising in cancer patients (Wu and Senter, Nat Biotechnol 2005, 23:1137-1146). However, a need exists for more effective methods and compositions for treatment of HIV-infected cells.